Blood circulation plays a cardinal role in heat-induced tissue damage since tissue temperature during heating and intratissue environment factors which affect thermal damage, such as pH and nutritional supply, are closely related to blood flow. The blood flow itself is markedly altered by heat, and thus how the blood flow is changed by heat directly dictates how the tissues are damaged by heat. The heat-induced changes in blood flow in the skin and muscle have been well documented. In contrast, little is known about the effects of heat on the blood flow in other normal tissues, particularly in internal organs. The first aim of the present proposal is to elucidate the effects of heat on the blood flow in major internal organs of rats. It has recently been demonstrated that the blood circulatory system adapts to heat-stress so that second and subsequent heatings are less effective than the first heating in changing the blood flow. Circumstantial evidence suggests that such vascular adaptation is due, at least in part, to development of vascular thermotolerance in the vessel walls. The second aim of this proposal is to obtain insight into the kinetics and magnitude of vascular thermotolerance in the normal tissues and R3230 Ac adenocarcinoma of rats. It has been suggested that tumor blood flow might be selectively reduced, and thus be preferentially heated in hyperthermia by using vasoactive compounds. The third aim is to continue our study on the change sin blood flow in various normal tissues and in R3230 Ac tumors grown in different sites by various vasoactive agents such as hydralazine, nitroprusside, flavone acetic acid (FAA) and Interleukin-1 (IL-1). We will then investigate the combined effects of heat and drugs on blood flow in normal tissues and tumors. The proposed studies using animal models would provide important information for the effective use of hyperthermia in the control of human cancer.